Nicotine formulation

ABSTRACT

The invention relates to a pharmaceutical formulation comprising nicotine. The formulation can be aerosolised at ambient temperature for delivery via inhalation. The invention also relates to a method of delivering nicotine to a subject via inhalation, and specifically via the use of a nebuliser.

TECHNICAL FIELD

The present invention relates to a pharmaceutical formulation comprisingnicotine and a high volume of water. The formulation can be aerosolisedat ambient temperature for delivery via inhalation. The invention alsorelates to a method of delivering nicotine to a subject via inhalation,and specifically via the use of a nebuliser. In alternative embodiments,the formulation can be delivered via a conventional e-cigarette device.

BACKGROUND

The serious health risks associated with smoking have been welldocumented. It is estimated that smoking tobacco, which comprises thealkaloid nicotine, is responsible for over seven million prematuredeaths a year (World Health Organisation), making it one of the leadingcauses of preventable death. Smoking also leads to diseases such asstenosis, lung cancer, and chronic obstructive pulmonary disease, whilesmoking during pregnancy can lead to miscarriage, premature birth,stillbirth and low birth weight and is reported to increase the risk ofcot death by at least 25%(https://www.nhs.uk/smokefree/why-quit/smoking-health-problems).Second-hand smoke, or passive smoking, causes more than 890 000premature deaths per year, many of them among children. However, it isnot the nicotine itself that is primarily harmful to health, but theby-products of tobacco smoke.

Nicotine replacement therapies (NRTs) are pharmaceutical therapies whichadminister nicotine by means other than smoking tobacco, while allowinga user to mimic the effect of cigarette smoking. NRTs are associatedwith increased success at smoking cessation compared with placebos(Silagy et al. “Nicotine replacement therapy for smoking cessation”,Cochrane Database of Systematic Reviews 2004; (3):CD000146). NRTstypically include transdermal patches, gums, oral and nasal sprays,inhalers, tablets and lozenges. However, NRTs suffer from a number ofdisadvantages, and primarily from inferior nicotine pharmacokinetic (PK)profiles when compared with combustible cigarettes (CCs).

Electronic cigarettes, or e-cigarettes, are handheld devices, often madeto look like conventional CCs, and can be used by smokers to mimic thesmoking action. E-cigarettes typically comprise a mouthpiece, acartridge, an atomiser, a microprocessor, and a battery. The cartridgecontains an e-liquid, which comprises the nicotine in viscous solventssuch as vegetable glycerine and propylene glycol. The e-liquid is heatedto high temperatures in the e-cigarette to form a vapour, which isinhaled by the user. The global use of e-cigarettes has increasedexponentially since their introduction into consumer markets in 2004,with estimated global sales of US$7 billion annually (World HealthOrganisation, Backgrounder on WHO report on regulation of e-cigarettesand similar products). However, known e-cigarettes often do not providea PK profile comparable to that of CCs, and as such do not reduce theurge to smoke for many users.

In addition, smoking of both conventional CCs and e-cigarettes involvesheating of the nicotine formulation in order to combust or vaporise theingredients for inhalation. This heating results in the generation ofundesirable by-products which are known to have an adverse effect onhealth. While the majority of toxic chemicals found in tobacco smokefrom conventional CCs are absent in e-cigarette vapour, e-cigarettesstill generate toxicants and traces of heavy metals (Hajek et al.Addiction. 2014 November; 109(11): 1801-1810). In addition, e-cigarettevapour can be inhaled passively by third parties.

It is an aim of the invention to obviate or mitigate one or more of thedisadvantages associated with the prior art. Ideally, it would beadvantageous to provide a nicotine formulation which exhibits a similarPK profile to a CC. A formulation which could be administered at ambienttemperatures would also be advantageous, as would be its mode ofdelivery. A reduction in the formation of deleterious side-productswould also be beneficial, whether administered at ambient orconventional e-cigarette temperatures, as would a reduction in thevapour cloud generated.

SUMMARY OF THE INVENTION

According to an aspect of the invention there is provided apharmaceutical formulation comprising 0.1-8% wt. % of nicotine; at least65 wt. % water; and one or more of flavouring agents, co-solubilisersand solubilisers; wherein the nicotine is the form of a nicotine salt ofnicotine and an acid; and wherein the pharmaceutical formulation has anacidic pH. The formulation may be an inhalable pharmaceuticalformulation.

According to another aspect of the invention there is provided a methodof delivering nicotine to a subject, comprising providing an aerosolisedformulation comprising 0.1-8% wt % of nicotine and at least 65 wt. %water; and administering the aerosolised formulation via inhalation. Themethod may comprise providing the formulation as a liquid and nebulizingthe liquid formulation to form an aerosolised formulation forinhalation.

Various further features and aspects of the invention are defined in theclaims.

BRIEF DESCRIPTION OF THE DRAWINGS

Embodiments of the present invention will now be described by way ofexample only with reference to the accompanying drawings where likeparts are provided with corresponding reference numerals and in which:

FIG. 1 shows venous blood plasma concentrations of nicotine pre- andpost-inhalation of a formulation according to the invention.

DETAILED DESCRIPTION

The present invention relates to a pharmaceutical formulation comprising0.1-8% wt % of nicotine; at least 65 wt. % water; and one or more offlavouring agents, co-solubilisers and solubilisers. The nicotine isincluded in the formulation in the form of a salt of nicotine and anacid, or salts of nicotine and an acid. The pharmaceutical formulationhas an acidic pH.

Advantageously, the formulation comprises high volumes of water. Thisresults in a decrease in the amount of deleterious side-productsproduced when the formulation is aerosolised, and subsequently inhaledby a subject. In addition, it advantageously appears that the highvolumes of water in the formulation lead to improved PK behaviour, withPK curves of the formulations according to the invention demonstratingcorrelation with those of CCs. A high water content also facilitatesaerosol production. In an embodiment, the formulation comprises at least70 wt. % of water. In another embodiment, the formulation comprises atleast 75 wt. % of water, or at least 80 wt. % of water.

Typical formulations for e-cigarettes comprise large volumes (˜>60%) ofviscous chemicals such as glycerine and propylene glycol. Heating tohigh temperatures is required to volatilize these components foradministration, resulting in the generation of harmful by-products. Inthe formulation of the present invention, however, low quantities ofsuch viscous chemicals are used. Specifically, the formulation of thepresent invention does not comprise viscous chemicals such as glycerineand propylene glycol in large quantities. In an embodiment, theformulation comprises less than 20%, and preferably less than 15% intotal of propylene glycol and glycerine.

Other known formulations comprise ingredients such as hydrofluorocarbons(HFCs), which are used in respiratory drug delivery. However, despitetheir relative widespread use as propellants, HFCs are known to haveadverse effects on the stratospheric ozone layer, and there are concernssurrounding their potential neurotoxicity (Ritchie G D et al., Acuteneurobehavioral effects in rats from exposure to HFC 134a or CFC 12;Neurotoxicology 22(2): 2001; pp. 233-248).

Advantageously, the high volumes of water in the formulation accordingto the invention mitigate the need to heat the formulation to hightemperatures for inhalation, resulting in a decrease in harmfulby-products. The formulation also avoids the use of HFCs, with theirassociated disadvantages. In an embodiment, the formulation of theinvention does not comprise hydrofluorocarbons.

According to the invention, the nicotine is included in the formulationat a concentration of from 0.1 to 8 weight %. Ideally, the formulationcan comprise varying amounts of nicotine to assist in smoking reductionor cessation in a user. In embodiments, the nicotine is included in theformulation at a concentration of from 0.1 to 5% of nicotine, or from0.1 to 3% of nicotine. Within this range, formulations comprising from0.3-0.6%, from 1-1.2%, from 1.6-1.9% and from 2.1-2.5% may be preferred.

Nicotine (3-(1-methyl-2-pyrrolidinyl)-pyridine) may benaturally-occurring nicotine, or may be a synthetic nicotine.

In the formulation the nicotine is included in the form of a salt. Thelower pH of the nicotine salt versus free base nicotine attenuates theirritating effect of the nicotine and results in a more palatableformulation. A single salt or a mixture of nicotine salts may be used.Suitable acids for forming the nicotine salt must exhibit minimal or notoxicity to humans.

Many suitable acids have poor solubility in water, but yield a solublesalt when mixed with the alkaline nicotine. When such poorly solubleacids are used, stoichiometric amounts of the acid are mixed with thenicotine to form a soluble product, before a water soluble acid is addedto adjust the pH.

In an embodiment, the acid is selected from acetic acid, acetylsalicylicacid, alginic acid, 2-aminoethanesulfonic acid (taurine),aminomethylphosphonic acid, arachidic acid, ascorbic acid, asparticacid, azelaic acid, barbituric acid, benzylic acid, benzoic acid,butanoic acid, butyric acid, capric acid, caproic acid, caprylic acid,carbonic acid, cinnamic acid, citric acid, decanoic acid, dodecanoicacid, enanthic acid, ethanoic acid, folic acid, formic acid, fumaricacid, gallic acid, gentisic acid, gluconic acid, glutamic acid, glutaricacid, heptanoic acid, hexanoic acid, hydrochloric acid, icosanoic acid,ketobutyric acid, lactic acid, lauric acid, levulinic acid, malic acid,maleic acid, malonic acid, margaric acid, methanoic acid,2-methylbutyric acid, 3-methylbutyric acid, 2-methyl propanoic acid,3,7-dimethyl-6-octenoic acid (citronellic acid), myristic acid,nonadecanoic acid, octanoic acid, oleic acid, oxalic acid, 2-oxobutyricacid, palmitic acid, pectic acid, pelargonic acid, pentadecanoic acid,pentanoic acid, phthalic acid, phenylacetic acid, picric acid, propanoicacid, propiolic acid, pyruvic acid, rosolic acid, salicyclic acid,sorbic acid, stearic acid, succinic acid, sulfosalicylic acid, tannicacid, tartaric acid, tetradecanoic acid, p-toluenesulfonic acid,tridecanoic acid, tridecylic acid, trifluoromethanesulfonic acid,undecanoic acid, undecylic acid, uric acid and valeric acid

In an embodiment, the acid is selected from lactic acid, acetylsalicylicacid, 2-aminoethanesulfonic acid (taurine), aminomethylphosphonic acid,arachidic acid, ascorbic acid, azelaic acid, barbituric acid, benzylicacid, butanoic acid, capric acid, caproic acid, caprylic acid, carbonicacid, cinnamic acid, decanoic acid, dodecanoic acid, enanthic acid,ethanoic acid, folic acid, fumaric acid, gluconic acid, glutaric acid,heptanoic acid, hexanoic acid, icosanoic acid, ketobutyric acid,levulinic acid, maleic acid, malonic acid, margaric acid, methanoicacid, 2-methylpropanoic acid (isobutyric acid), 3,7-dimethyl-6-octenoicacid (citronellic acid), myristic acid, nonadecanoic acid, nonadeclylicacid, octadecanoic acid, octanoic acid, oleic acid, 2-oxobutyric acid,pelargonic acid, pentadecanoic acid, pentadecylic acid, pentanoic acid,propanoic acid, propiolic acid, rosolic acid, sorbic acid, stearic acidand succinic acid, tetradecanoic acid, p-toluenesulfonic acid,tridecanoic acid, tridecylic acid, trifluoroacetic acid,trifluoromethanesulfonic acid, undecanoic acid, undecylic acid and uricacid.

In an embodiment, the acid is lactic acid. Lactic acid is anaturally-occurring organic acid and is native to the human body, makingit suitable for use in the pharmaceutical formulation of the invention.

In an alternative embodiment, the acid is 2-methylpropanoic acid(isobutyric acid). Isobutyric acid imparts a dairy/cheesy flavoured noteto the formulation, thereby improving palatability and thereforeisobutyric acid, along with butyric acid which has a similar effect, isparticularly suitable for use in the present invention.

In an alternative embodiment, the acid is benzoic acid.

The pharmaceutical formulation has an acidic pH. Advantageously, whenthe formulation has an acidic pH, nicotine can be readily absorbed intothe lungs.

In an embodiment, the formulation has a pH of from 4.5 to 6.5.

In an embodiment, the formulation has a pH of from 4.5 to 5.9.

In an embodiment, the formulation has a pH of from 5.0 to 5.8.

The pH of the formulation is typically adjusted as required using anexcess of the acid used to form the nicotine salt. When a poorly solubleacid is used to form the salt, another, water-soluble acid may be usedto adjust the pH.

In an embodiment, the formulation does not include a separate bufferingagent or pH regulating agent.

In an embodiment, the formulation comprises at least 75% of water. In anembodiment, the formulation comprises at least 77% of water. As notedabove, high volumes of water can facilitate aerosol production and leadto improved PK characteristics. The formulation also leads to little orno observable vapour “cloud” being produced when the product is exhaled,lessening the impact of passive smoking on third parties.

In an embodiment, the formulation is a liquid formulation. In anembodiment, the formulation is provided as a liquid formulation. Forinstance, the liquid formulation can be provided in a cartridge, for usewith an aerosolising or nebulizing device such as an e-cigarette,nebulizer or metered-dose inhaler [MDI].

In an embodiment, the formulation is in the form of aerosoliseddroplets.

Mass Median Aerodynamic Diameter (MMAD) refers to the diameter at which50% of the particles by mass are larger, and 50% of the particles bymass are smaller. The size of the droplets determines the site ofdeposition of the particles in the respiratory tract. In an embodiment,the aerosolised droplets may have an MMAD of from 1 to 6 μm. In anembodiment, the aerosolised droplets may have an MMAD of from 2 to 4 μm.When the MMAD is within these ranges, the aerosolised droplets are smallenough to avoid irritating the back of the throat, but large enough tosettle in terminal bronchi and alveoli rather than simply being exhaled,facilitating deep lung delivery. Advantageously, the high volume ofwater in the formulation of the invention facilitates the formation ofsuch small droplets, and consequently delivery to the deep lung. Thisdeep lung delivery can lead to a sense of smoking satisfaction in users.

In an embodiment, the formulation comprises one or more flavouringagents. The flavouring agent may be a natural flavouring agent or anartificial or simulated flavouring agent, and combinations of flavouringagents can be used. Suitable flavouring agents for use innicotine-containing products are known in the art. Examples of suitableflavouring agents include fruit flavours such as apple, banana,bergamot, cherry, grape, lemon, orange, pear, pineapple, raspberry andstrawberry; plant flavours such as vanilla, nut flavours such ashazelnut; spice flavours such as cinnamon and clove; root flavours suchas ginger and liquorice, mint flavours such as menthol, eucalyptol andpinene; and tobacco flavours.

In an embodiment, the formulation comprises a tobacco, fruit or mintflavouring.

In an embodiment, the flavouring agent is a water-soluble flavouringagent. In an embodiment, the flavouring agent is selected from aceticacid, 2-acetylpyridine, 3-acetylpyridine, 2-acetyl-5-methylfuran,α-angelica Lactone (5-methyl-3H-furan-2-one),4,5-dimethyl-3-hydroxy-2,5-dihydrofuran-2-one, 2,5-dimethylpyrazine,2,6-dimethylpyrazine, ethyl acetate, 2-ethyl-3(5 or 6)-dimethylpyrazine,ethyl-3-hydroxybutyrate, 5-ethyl-3-hydroxy-4-methyl-2(5H)-furanone,5-ethyl-4-hydroxy-2-methyl-3(2H)-furanone, ethyl maltol,2-ethyl-3(5)-dimethylpyrazine, 2-ethyl-3(6)-dimethylpyrazine, furaneol,4-hydroxy-2,5-dimethyl-3(2H)-furanone, 2-furanmethanethiol formate,furfural (2-Furaldehyde), furfuryl alcohol, furfuryl mercaptan,2,3-hexanedione, Y-hexalactone, homo furaneol(4-hydroxy-5-ethyl-2-methyl-3(2H)-furanone), 4-hydroxybutanoic acidlactone, 4-hydroxy-2,5-dimethyl-3(2H)-furanone,4-hydroxy-5-methyl-3-furanone, isobutyraldehyde, malic acid, maltol((3-hydroxy-2-methyl-4H-pyran-4-one), methional(3-methylsulfanylpropanal), methyl acetate, methyl cyclopentenolone(3-methylcyclopentane-1,2-dione), methyl cyclopentenolone (hydrate),5-methylfurfural, methyl nicotinate, 4-methyl-5-thiazoleethanol,neohesperidin dihydrochalcone, 2-oxobutyric acid, 4-oxoisophorone(2,6,6-trimethyl-2-cyclohexene-1,4-dione), propionaldehyde,pyruvaldehyde, triacetin, 2,6,6-trimethyl-2-cyclohexene-1,4-dione and2,4,5-trimethylthiazol, 2,3,5-trimethyl pyrazine, vanillyl alcohol.

Alternatively, the flavouring agent may be a flavouring oil, such as anatural flavouring essential oil. Such oils include, but are not limitedto ajwain oil, angelica root oil, anise oil, asafoetida, balsam of Peru,basil oil, bay oil (Laurus nobilis), bergamot oil, black pepper, buchuoil, cannabis flower essential oil, calamodin oil, caraway seed oil,cardamom seed oil, carrot seed oil, cedar oil, chamomile oil, cinnamonoil, citron oil, citronella oil, clary sage oil, coconut oil, clove oil,coffee oil, coriander oil, costmary oil, costus root oil, cranberry seedoil, cubeb oil, cumin seed oil, cypriol oil, curry leaf oil, dill oil,elecampane oil, eucalyptus oil, fennel seed oil, fenugreek oil, galangaloil, garlic oil, geranium oil, ginger oil, goldenrod oil, grapefruitoil, helichrysum oil, hickory nut oil, horseradish oil, hyssop, juniperberry oil, lavender oil, ledum, lemon oil, lemongrass, lime, limonene,linalool, mandarin, marjoram, melissa oil (lemon balm), Mentha arvensisoil, mountain savory, myrrh oil, myrtle, neroli, nutmeg oil, orange oil,oregano oil, orris oil, palo santo, parsley oil, peppermint oil,petitgrain, pine oil, ravensara, Roman chamomile, rose oil, rosehip oil,rosemary oil, sage oil, star anise, sassafras oil, schisandra oil,spearmint oil, spikenard, spruce oil, star anise oil, tangerine, tansy,tarragon oil, thyme oil, turmeric, valerian, wintergreen, yarrow oil andzedoary oil.

However, the flavouring agent is not particularly limited, and othersuitable flavouring agents would be known to a person skilled in theart. In an embodiment, the formulation comprises one or moreco-solubilisers. Suitable co-solubilisers include, but are not limitedto propylene glycol, polyethylene glycol (PEG), glycerine, polyethyleneglycol (PEG)/polypropylene glycol (PPG) co-polymers,polyvinylpyrrolidone, 1,2-hexanediol, 1,2-pentanediol, diethylene glycolmono-ethyl ether, dimethyl isosorbide, ethanol, n-butanol, n-pentanol;and mixtures thereof. In an embodiment, the co-solubiliser is propyleneglycol, glycerine, or a mixture of propylene glycol and glycerine.

In an embodiment, the formulation comprises one or more solubilisers.Suitable solubilisers include, but are not limited to, polyoxyethylene(40) castor oil, poloxamer 407™ (poly(ethyleneglycol)-block-poly(propylene glycol)-block-poly(ethylene glycol),polyoxyl (35) castor oil, polyoxyl (40) castor oil, polyoxyl (40) castoroil in admixture with PPG-1-PEG 9 lauryl glycol ether, PEG (40) castoroil, PPG-1-PEG 9 lauryl glycol ether, polyoxyethylated 12-hydroxystearicacid, PEG 300, PEG 400, dioleic acid PEG 600 ester, heptyl glucoside,isostearic acid monoisopropanolamide, coconut fatty acid diethanolamide,coconut fatty acid glycol ester, coconut fatty acid monoethanolamide,coconut fatty acid PEG200 ester, coconut fatty acid PEG600 ester, oleicacid PEG600 ester, oleic acid C12-C14 alkylester, oleic aciddiethanolamide, oleic acid monoisopropanolamide, oleic acid PEG1000ester, oleic acid PEG200 ester, rape seed oil diethanolamide, tall oilfatty acid diethanolamide, tall oil fatty acid monoisopropanolamide,tall oil PEG200 ester, tall oil PEG600 ester, polysorbate 20,polysorbate 40 (polyoxyethylene sorbitan monopalmitate/Tween™ 40),polysorbate 60, polysorbate 65, polysorbate 80 (Tween™ 80), polysorbate85, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate,sorbitan monooleate, sorbitan monoisostearate, sorbitan tristearate;Cosmacol™ N119 (C12-C13 Pareth 9); and mixtures thereof.

In an alternative embodiment, suitable solubilisers include, but are notlimited to, polyoxyethylene (40) castor oil, poloxamer 407™(poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethyleneglycol), polyoxyl (35) castor oil, polyoxyl (40) castor oil, polyoxyl(40) castor oil in admixture with PPG-1-PEG 9 lauryl glycol ether, PEG(40) castor oil, PPG-1-PEG 9 lauryl glycol ether, polyoxyethylated12-hydroxystearic acid, PEG 300, PEG 400, dioleic acid PEG 600 ester,heptyl glucoside, isostearic acid monoisopropanolamide, coconut fattyacid diethanolamide, coconut fatty acid glycol ester, coconut fatty acidmonoethanolamide, coconut fatty acid PEG200 ester, coconut fatty acidPEG600 ester, oleic acid PEG600 ester, oleic acid C12-C14 alkylester,oleic acid diethanolamide, oleic acid monoisopropanolamide, oleic acidPEG1000 ester, oleic acid PEG200 ester, rape seed oil diethanolamide,tall oil fatty acid diethanolamide, tall oil fatty acidmonoisopropanolamide, tall oil PEG200 ester, tall oil PEG600 ester,polysorbate 20, polysorbate 40 (polyoxyethylene sorbitanmonopalmitate/Tween™ 40), polysorbate 60, polysorbate 65, polysorbate85, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate,sorbitan monooleate, sorbitan monoisostearate, sorbitan tristearate;Cosmacol™ N119 (C12-C13 Pareth 9); and mixtures thereof.

In an embodiment, the solubiliser is PEG (40) hydrogenated castor oil.

In an embodiment, the formulation comprises one or more sweeteners.Suitable sweeteners include oxathiazinone sweeteners such as acesulfameand acesulfame K; dipeptide derivatives such as Alitame™, aspartame andaspartame derivatives and aspartame-like di- and tri-peptides such asneotame; sulfamates such as sodium cyclamate(sodium-N-cyclohexylsulfamate) and calcium cyclamate; sugar alcoholssuch as erythritol, xylitol, maltitol, mannitol, sorbitol, isomalt andtagatose; naturally occurring sweeteners such as xylose, glycyrrhizinand stevia; rare sugars such as d-psicose and d-allose; saccharin,sucralose, gluonic acid; and mixtures thereof.

In an embodiment, the formulation is an inhalable formulation.

By “inhalable formulation” is meant that the formulation is in the formof droplets suitable for inhalation by a subject. For instance, the MMADof the droplets may be 12 μm or less, or the MMAD of the droplets may be10 μm or less. In an embodiment, the MMAD is between 1 to 6 μm, orbetween 2 and 4 μm. The inhalable formulation can be obtained byaerosolising the liquid formulation previously described, for instancein a nebulizer.

Further ingredients such as suspending agents, thickening agents and/orexcipients can be included in the formulation. The inclusion of suchadditional components would be within the remit of one skilled in theart.

In an embodiment, the pharmaceutical formulation comprises from 75 to 85wt. % of water; from 0.1 to 8 wt. % of nicotine; from 0.1 to 15 wt. % ofco-solubiliser; from 0.5 to 1.5 wt. % of sweetener; from 0.05 to 1.5 wt.% of flavouring; and from 1 to 5% of acid. In an embodiment, thenicotine is included at from 0.1 to 5%. In an embodiment, the acid isincluded at from 1 to 2%.

In an embodiment, the pharmaceutical formulation comprises from 75 to 85wt. % water; from 0.1 to 8 wt. % nicotine; from 0.1 to 15 wt. %co-solubiliser; from 0.5 to 1.5 wt. % sweetener; and from 0.05 to 1.5wt. % of flavouring. Preferably, the pharmaceutical formulationcomprises >80 wt. % of water.

According to an aspect of the invention, there is provided a method ofdelivering nicotine to a subject, comprising providing an aerosolisedformulation comprising 0.1-8% wt. % of nicotine and at least 65 wt. %water; and administering the aerosolised formulation via inhalation. Theformulation may be the formulation described in detail above.

The method may further comprise providing the formulation in liquidform, and nebulising or aerosolising the liquid formulation to form theaerosolised formulation. For instance, the formulation may be suppliedas a liquid, in a cartridge or similar, for use with a nebuliser.Accordingly, in an aspect of the invention there is provided a cartridgecomprising the liquid formulation, and an e-cigarette or nebuliserdevice comprising the liquid formulation or aliquid-formulation-containing cartridge.

The liquid formulation may be nebulised via the application of oxygen,compressed air or ultrasonic power to form the aerosolised formulation.In an embodiment, the nebuliser is a mechanical nebuliser, a jetnebuliser, a mesh nebuliser such as a vibrating mesh nebuliser or anultrasonic nebuliser such as a piezo or PZT nebuliser. In an embodiment,the nebuliser is a mesh nebuliser.

EXAMPLES

Methodology:

Viscosity was measured using a Cannon-Penske viscometer. The viscometeris first cleaned with deionized water followed by pure ethanol which isallowed to drain away, before the device is dried in a current of air.The viscometer is charged with the test-liquid by pouring it into thewider bored tube of the U-shaped apparatus until the large bulbreservoir is half-full. The viscometer is placed in a thermostatted bathand temperature allowed to equilibrate. The viscometer is carefullylevelled, and the liquid drawn by pipette filler through the capillaryof the narrower tube until the level reaches above a first fixedgradation mark. The pipette filler is carefully removed, and the liquidlevel allowed to fall to the first fixed gradation mark, at which pointa stopwatch is activated. The time taken for the level to fall to asecond, lower graduated mark is recorded. The procedure is repeated fouradditional times and the average time calculated.

The kinematic viscosity, ν, measured in mm²/s, is calculated bymultiplying the average time by the viscosity constant—which is suppliedwith each individual viscometer.

The invention will now be described with reference to the followingnon-limiting examples:

Example 1: Preparation of Formulation

A formulation comprising 0.3% (w/w) of nicotine was prepared as set outbelow. All non-nicotine ingredients used were of food-grade quality.

A stock solution of 5% w/w sucralose was prepared by adding 5.0 g ofsucralose to 95.0 g of water. The mixture was stirred vigorously until aclear solution remained.

A flavour complex consisting of a mixture of 0.025 g of5-ethyl-3-hydroxy-4-methyl-2(5H) furanone and 0.05 g of cis 3-hexen-1-olwas dissolved in propylene glycol sufficient to give 5 g of solution.

0.025 g of L-menthol was added to 1.0 g of Kolliphor™ RH-40 and themixture was stirred until clear. This was added to the flavour complexalong with 2.50 g of the 5% sucralose solution.

Separately, 0.30 g of nicotine was weighed into a beaker and dissolvedin 90.67 g of water. 0.1 g of mannitol, followed by 0.1 g ofsodium-N-cyclohexylsulphamate, was dissolved in the solution. The pH ofthe formulation was measured using a pH meter (Jenway 3510). 0.166 g oflactic acid was added to form a salt with nicotine (1:1 ratio). Excesslactic acid was then added dropwise until the pH of the solution reached5.5.

The nicotine solution was added to the flavouring solution and themixture stirred until homogeneous. A residual of 0.85 g of water wasadded.

Solutions comprising 0.6%, 1.2%, 1.8%, 2.4% and 5% (designated F #1 to F#5) of nicotine were prepared in the same manner.

The composition of the formulations is shown in Table 1 below:

TABLE 1 Nicotine formulations F# 1 F#2 F#3 F#4 F#5 Component Wt. % Wt. %Wt. % Wt. % Wt. % Water 83.17 82.36 81.32 80.28 75.77 Propylene glycol11.1 11.1 11.1 11.1 11.1 PEG (40) hydrogenated 0.50 0.50 0.50 0.50 0.50castor oil Flavouring 1.10 1.10 1.10 1.10 1.10 Glycerine 2.10 2.10 2.102.10 2.10 Stevia 0.26 0.26 0.26 0.26 0.26 Sucralose 0.25 0.25 0.25 0.250.25 Na N-cyclohexyl- 0.10 0.10 0.10 0.10 0.10 sulphamate Mannitol 0.150.15 0.15 0.15 0.15 Nicotine 0.60 1.2 1.8 2.4 5.0 Lactic acid 0.67 0.881.32 1.76 3.67 pH 5.5 5.5 5.5 5.5 5.5

Example 2

A formulation was prepared according to the same methodology as Example1, comprising the following:

TABLE 2 Nicotine formulation Component Wt. % Water 80.45 Nicotine 3.6Lactic acid 2.6 Sucralose 0.1 Pyruvaldehyde 1.0 Glycerine 12.25

The formulation had a pH of 5.

The viscosity of the formulation was then measured as follows:

The product, a red-brown liquid was evaluated for viscosity using theCannon-Penske viscometer, supplied by PSL Rheotek, and its relativedensity determined using a 25 ml relative density bottle.

The formulation was found to have a kinematic viscosity of 1.866m²/s×10⁻⁶ cS. Its relative density was 1.048 g/ml. Its dynamic viscositywas therefore 1.956 cP.

Pharmacokinetic Study:

Nicotine formulations comprising 1.2, 1.8 and 2.4% of nicotine wereprepared as outlined above, with the concentrations chosen to encompasssome of the doses likely to be acceptable to users.

4 Healthy volunteers (male & female) aged 18-55 years were eligible forthe study if they had smoked manufactured cigarettes or vaped every dayfor the last year and typically smoked their first cigarette within 1hour of waking.

All subjects were required to abstain from smoking for 12 hr prior totheir scheduled dosing time. Participants were excluded if they had aknown or suspected history of hypersensitivity to nicotine or any othercomponent of the inhaler. Participants were also excluded if they had ahistory of confirmed chronic and/or serious pulmonary disease, includingasthma, or chronic obstructive pulmonary disease, a history ofmyocardial infarction or cerebrovascular accident, other clinicallysignificant cardiac or renal conditions, or any comorbidity that couldplace them at risk or interfere with the interpretation of the studydata. Women who were breastfeeding were excluded from the study.

Participants were familiarized with the inhaler device using a placeboformulation on the day prior to receiving active treatment. The placeboformulation was identical to the active formulation described above,with the exception that the placebo formulation did not includenicotine.

The nicotine inhaler device used was a MicroBase™ Pocket AirNeb MiniPortable Nebuliser [Model No. MBPN002]. This device comprises a portablecompact compressor with small delivery mouthpiece that allows a user toinhale. The average nebulization rate is >0.25 ml/min, and respirableoutput of MMAD 4 μm. Nicotine is delivered from each inhale, and levelof nicotine is therefore dependent on an individual's depth ofinhalation and number of “puffs” over the time span of 3 minutes+/−30secs.

The device was filled with the formulations described above.Participants inhaled each time in a similar way to a cigarette. Allparticipants were instructed to inhale at the same rate of oneinhalation every 20 s+/−5 secs over approximately 3 min (i.e.,approximately eight inhalations in total). This inhalation protocolshould comprise a comparable inhalation to that of a CC for most users.

As a control, venous blood samples were collected 5 min pre-dose.Samples were then collected at 2, 4, 6, 8, 10, 15 and 20 minutes (+/−2mins) post-dose (i.e., from the start of inhalation) for the measurementof plasma nicotine concentration by a liquid chromatography with tandemmass spectrometry method that was validated for linearity and precision.

The results of this study are shown in FIG. 1 . The intervals varyslightly (i.e. +/−2 mins) due to human variation in obtaining the sample(i.e. the time to insert the needle etc.).

Venous plasma nicotine concentration post-inhalation of a CC is shown by(●). The CC profile shows a rapid increase in plasma nicotine levelsover the first 8 minutes, reaching a plateau at about 20 minutes. Thenicotine formulation of the invention showed a similar profile,particularly for the formulations comprising 1.8 and 2.4% of nicotine.

This data suggests that nicotine is rapidly entered into systemiccirculation following inhalation of the formulation of the invention andexhibits a similar pharmacokinetic profile to CCs. This was borne out bythe responses to the trial with users noting a high degree ofsatisfaction following inhalation of the formulation.

Users also visibly observed a lack of vapour cloud when exhaling theformulation of the invention.

Degradation Study:

Conventional e-cigarette liquids comprising viscous carriers such aspropylene glycol and glycerine are suspected of generating trace levelsof various toxins during vaporization. Tayyarah et al. (Reg. Toxicol.Pharmacol. 70 (2014): 704-710 determined the total carbonyls generatedduring vaporization for a series of commercial e-cigarette liquids. Thecarbonyls, including formaldehyde, acetaldehyde, acrolein,propionaldehyde, crotonaldehyde, methyl ethyl ketone and butyraldehyde,were typically found to be present at values between <0.05 to <0.09 mgper 99 puffs, indicating that although exposure is more limited than forconventional cigarettes, low levels of toxins are still present.

In order to determine degradation of the formulation of the presentinvention, the following composition was prepared and tested:

TABLE 3 Nicotine formulation for degradation testing Component Wt. %Water 80.37 Nicotine 2.20 Lactic acid 1.70 Sucralose 0.134-hydroxy-5-methyl-furanone 0.60 Glycerine 15.00

The formulation had a pH of 5.5.

The degradation study was carried out as follows:

The formulation of table 3 was analysed for known toxic compounds, andthe results for this reference sample are shown below. The formulationwas then vaporised using 1) a conventional heated e-cigarette device(which heats to 260° C.-280° C.); and 2) a portable nebulizer (PocketAir® from Microbase Technology Corporation), in which the vapour isgenerated without heating, i.e. at ambient temperature. Volatile organiccompounds (VOCs) present in the resulting formulation vapour wereanalysed by assaying a single 100 ml puff trapped in a suitable solidsupport containing 2,4-dinitrophenylhydrazine (DNPH) which was elutedand analysed by HPLC-DAD, using UV, RI and PDA detectors.

HPLC-DAD Conditions were as follows:

-   -   Column: C18 Atlantis    -   Temperature: 35° C.    -   Analysis Time: 10 min    -   Injection Vol: 20 μl    -   Detection: PDA, UV and RI    -   Eluent: 50:50 acetonitrile:water containing 0.1% triethylamine.

The results of the study are shown in Table 4 below:

TABLE 4 Results of degradation testing Reference Conventional e- AmbientCompound Sample cigarette heating temperature Nicotine  2.21 ± 0.1790.020 ± 0.002 0.022 ± 0.002  Propylene Glycol N.D.* N.D.* N.D.*Glycerine 10.05 ± 1.23  0.0012 ± 0.0001 0.001 ± 0.0001 Diethylene GlycolN.D.* N.D.* N.D.* Ethylene Glycol N.D.* N.D.* N.D.* Acetone N.D.* N.D.*N.D.* Acetoin N.D.* N.D.* N.D.* Diacetyl N.D.* N.D.* N.D.*2,3-Pentanedione N.D.* N.D.* N.D.* (acetyl propionyl) Propylene OxideN.D.* N.D.* N.D.* Acrolein N.D.* N.D.* N.D.* Formaldehyde N.D.* N.D.*N.D.* Acetaldehyde N.D.* N.D.* N.D.* N.D.* = Not detected

Results demonstrate that there were no detectable levels of conventionale-cigarette toxins in the vapour of the formulation, irrespective ofmode of delivery, suggesting that the formulation of the presentinvention shows a reduction in the formation of deleterious by-products,at both ambient and conventional e-cigarette temperatures.

All of the features disclosed in this specification (including anyaccompanying claims, abstract and drawings), and/or all of the steps ofany method or process so disclosed, may be combined in any combination,except combinations where at least some of such features and/or stepsare mutually exclusive. Each feature disclosed in this specification(including any accompanying claims, abstract and drawings) may bereplaced by alternative features serving the same, equivalent or similarpurpose, unless expressly stated otherwise. Thus, unless expresslystated otherwise, each feature disclosed is one example only of ageneric series of equivalent or similar features. The invention is notrestricted to the details of the foregoing embodiment(s). The inventionextends to any novel one, or any novel combination, of the featuresdisclosed in this specification (including any accompanying claims,abstract and drawings), or to any novel one, or any novel combination,of the steps of any method or process so disclosed.

The invention claimed is:
 1. A liquid pharmaceutical formulation,comprising: 0.1-8% wt. % of nicotine; at least 65 wt. % water; and oneor more of flavouring agents, co-solubilisers and solubilisers; whereinthe formulation comprises a co-solubiliser and/or a solubiliser; whereinthe nicotine is the form of a nicotine salt of nicotine and an acid;wherein the acid is selected from lactic acid, 2-methylpropanoic acid,acetylsalicylic acid, 2-aminoethanesulfonic acid (taurine),aminomethylphosphonic acid, arachidic acid, ascorbic acid, azelaic acid,barbituric acid, benzoic acid, benzylic acid, butanoic acid, capricacid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,decanoic acid, dodecanoic acid, enanthic acid, ethanoic acid, folicacid, fumaric acid, gluconic acid, glutaric acid, heptanoic acid,hexanoic acid, icosanoic acid, ketobutyric acid, maleic acid, malonicacid, margaric acid, methanoic acid, 3,7-dimethyl-6-octenoic acid,myristic acid, nonadecanoic acid, nonadeclylic acid, ocatadecanoic acid,octanoic acid, oleic acid, 2-oxobutyric acid, pelargonic acid,pentadecanoic acid, pentadecylic acid, pentanoic acid, propanoic acid,propiolic acid, quinic acid, rosolic acid, stearic acid and succinicacid, tetradecanoic acid, p-toluenesulfonic acid, tridecanoic acid,tridecylic acid, trifluoroacetic acid, trifluoromethanesulfonic acid,undecanoic acid, undecylic acid and uric acid; wherein thepharmaceutical formulation has a pH of from 4.5 to 5.9; wherein theformulation does not include a separate buffering agent or pH regulatingagent; and wherein the liquid pharmaceutical formulation isaerosolisable to form an inhalable formulation.
 2. A pharmaceuticalformulation as claimed in claim 1, comprising at least 75% water.
 3. Apharmaceutical formulation as claimed in claim 1, wherein theformulation is in the form of aerosolised droplets.
 4. A pharmaceuticalformulation as claimed in claim 1, wherein: (i) the formulationcomprises a flavouring agent, optionally wherein the flavouring agent isa tobacco, mint or fruit flavouring; and/or (ii) wherein the formulationadditionally comprises a sweetener.
 5. A pharmaceutical formulation asclaimed in claim 1, wherein the formulation comprises a co-solubiliserselected from propylene glycol, polyethylene glycol, glycerine,polyethylene glycol/polypropylene glycol co-polymers,polyvinylpyrrolidone, 1,2-hexanediol, 1,2-pentanediol, diethylene glycolmono ethyl ether, dimethyl isosorbide, ethanol, n-Butanol n-Pentanol,and mixtures thereof.
 6. A pharmaceutical formulation as claimed claim1, wherein the formulation comprises a solubiliser selected frompolyoxyethylene (40) castor oil, poly(ethyleneglycol)-block-poly(propylene glycol)-block-poly(ethylene glycol),polyoxyl (35) castor oil, polyoxyl (40) castor oil, polyoxyl (40) castoroil in admixture with PPG-1-PEG 9 lauryl glycol ether, PPG-1-PEG 9lauryl glycol ether, polyoxyethylated 12-hydroxystearic acid, PEG 300,PEG 400, dioleic acid PEG 600 ester, heptyl glucoside, isostearic acidmonoisopropanolamide, coconut fatty acid diethanolamide, coconut fattyacid glycol ester, coconut fatty acid monoethanolamide, coconut fattyacid PEG200 ester, coconut fatty acid PEG600 ester, oleic acid PEG600ester, oleic acid C12-C14 alkylester, oleic acid diethanolamide, oleicacid monoisopropanolamide, oleic acid PEG1000 ester, oleic acid PEG200ester, rape seed oil diethanolamide, tall oil fatty acid diethanolamide,tall oil fatty acid monoisopropanolamide, tall oil PEG200 ester, talloil PEG600 ester, polysorbate 20, polysorbate 40 (polyoxyethylenesorbitan monopalmitate, polysorbate 60, polysorbate 65, polysorbate 80,polysorbate 85, sorbitan monolaurate, sorbitan monopalmitate, sorbitanmonostearate, sorbitan monooleate, sorbitan monoisostearate, sorbitantristearate, C12-C13 Pareth 9 and mixtures thereof.
 7. A pharmaceuticalformulation as claimed in claim 1, the formulation comprising: from 75to 85 wt. % water; from 0.1 to 8 wt. % nicotine; from 0.1 to 15 wt. %co-solubiliser; from 0.5 to 1.5 wt. % sweetener; from 0.05 to 1.5 wt. %of flavouring.
 8. A method of delivering nicotine to a subject,comprising: providing an aerosolised formulation comprising 0.1-8% wt. %of nicotine; at least 65 wt % water; and one or more of flavouringagents, co-solubilisers and solubilisers; wherein the formulationcomprises a co-solubiliser and/or a solubiliser; wherein the nicotine isthe form of a nicotine salt of nicotine and an acid, wherein the acid isselected from lactic acid, 2-methylpropanoic acid, acetylsalicylic acid,2-aminoethanesulfonic acid (taurine), aminomethylphosphonic acid,arachidic acid, ascorbic acid, azelaic acid, barbituric acid, benzoicacid, benzylic acid, butanoic acid, capric acid, caproic acid, caprylicacid, carbonic acid, cinnamic acid, decanoic acid, dodecanoic acid,enanthic acid, ethanoic acid, folic acid, fumaric acid, gluconic acid,glutaric acid, heptanoic acid, hexanoic acid, icosanoic acid,ketobutyric acid, maleic acid, malonic acid, margaric acid, methanoicacid, 3,7-dimethyl-6-octenoic acid, myristic acid, nonadecanoic acid,nonadeclylic acid, ocatadecanoic acid, octanoic acid, oleic acid,2-oxobutyric acid, pelargonic acid, pentadecanoic acid, pentadecylicacid, pentanoic acid, propanoic acid, propiolic acid, quinic acid,rosolic acid, stearic acid and succinic acid, tetradecanoic acid,p-toluenesulfonic acid, tridecanoic acid, tridecylic acid,trifluoroacetic acid, trifluoromethanesulfonic acid, undecanoic acid,undecylic acid and uric acid; wherein the formulation does not include aseparate buffering agent or pH regulating agent; and wherein thepharmaceutical formulation has a pH of from 4.5 to 5.9; andadministering the aerosolised formulation via inhalation.
 9. A method ofdelivering nicotine to a subject as claimed in claim 8, wherein themethod further comprises providing a liquid formulation comprising0.1-8% wt. % of nicotine and at least 65 wt. % water; and nebulising theliquid formulation to form the aerosolised formulation; optionallywherein the liquid formulation is nebulised via the application ofoxygen, compressed air or ultrasonic power to form the aerosolisedformulation.
 10. A cartridge for use with an e-cigarette, wherein thecartridge comprises the formulation according to claim
 1. 11. Ane-cigarette comprising a cartridge as claimed in claim
 10. 12. Apharmaceutical formulation as claimed in claim 1, wherein the acid islactic acid.
 13. A pharmaceutical formulation as claimed in claim 5,wherein the co-solubiliser is propylene glycol, glycerine, or a mixturethereof.